The oral route remains the preferred route of drug administration due to its convenience and good patient compliance. Major problems in oral drug formulations are the erratic and incomplete absorption throughout the gastro-intestinal (GI) tract, resulting in low and variable bioavailability and lack of dose proportionality. These problems mainly result from poor aqueous solubility of the active ingredient. It has been reported that an estimated of existing pharmaceutical active ingredients and an even higher proportion of all newly developed drugs are poorly soluble or insoluble in water. This poses a major challenge to drug development, as there is a high need for producing suitable formulations to improve the solubility and bioavailability of such drugs.
Much research has been conducted into methods to cope with these problems. Methods that have been developed include the reduction of particle size of the drug by micronisation or nanonisation as to increase surface area, thereby increasing dissolution rate of the active ingredient. Further methods include solubilization in surfactant systems, water-soluble molecular complexes with cyclodextrins, converting the drug in amorphous form by lyophilization or formation of solid dispersions in hydrophilic carriers, microencapsulation, and the release from porous carrier materials.
One technique for promoting dissolution properties and oral bioavailability of poorly water-soluble drugs is by using them in liquid phase by dissolution or emulsion in non-volatile oils/lipids. Such systems have been referred to as lipid based drug delivery system (LBDDS). In these forms the active ingredient is already in solution so that the drug is present on molecular level, avoiding the dissolution step from the crystalline state. The drugs in liquid phase are typically filled into soft gelatin capsules. The latter give rise to drawbacks, such as complications in manufacturing, low manageability and portability, risks of leakage, limited shelf-life due to stability problems during storage caused by interactions between the components, oxidation of the lipid components, issues of compatibility of the liquid formulation with the capsule shell, criticality of storage temperature because of irreversible drugs/excipients precipitation at lower temperatures.
To overcome these problems, so-called liquisolid formulations have been developed, which are porous carrier materials wherein the drugs remain in liquid form. Liquisolid forms are obtained by conversion of drugs in liquid form into acceptably flowing non-adherent and compressible powder mixtures by blending with selected carriers and coating materials. These then are converted into solid dosage forms such as tablets, pellets, and capsules.
Due to increased wetting and surface area for dissolution, liquisolid dosage forms of water insoluble drugs show improved dissolution properties and bioavailability. This technique was successfully applied for low dose water-insoluble drugs. However, as loadability and release of the drugs from the carriers used is limited, formulation of insoluble drugs at higher doses is one of the limitations of the liquisolid technique. Another problem associated with liquisolid formulations is their decreased flowability when loaded with higher amounts of drugs in liquid form. This causes these materials difficult to process in pharmaceutical manufacturing. In order to have acceptable flowability and compactability, high levels of carrier and coating materials have to be added thereby increasing the weight and volume of the resulting dosage forms.
One type of lipid based drug delivery systems are the self-emulsifying drug delivery systems (SEDDS). This type of emulsion-based drug formulations can be used in soft gelatin capsules or as liquisolid formulations. SEDDS are isotropic and thermodynamically stable mixtures of drug, surfactant/cosurfactant, that, in contact with aqueous fluids, spontaneously form oil-in-water emulsions of droplets, ranging in droplet size approximately between 100-300 nm. Systems forming emulsions with droplets of less than 50 nm are referred to as self-micro-emulsifying drug delivery systems (SMEDDS), and even smaller droplet sizes as self-nanoemulsifying drug delivery system (SNEDDS). Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, where the digestive motility of the stomach and the intestine provide the agitation necessary for selfemulsification. These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDSs are physically stable formulations that are easy to manufacture. In particular for lipophilic drugs that exhibit limited and distorted absorption, these systems offer an improvement in the rate and extent of absorption resulting in more reproducible bioavailability.
Given the advantages of solid dosage forms, SEDDS, SNEDDS and SMEDDS have also been converted into solid-SEDDS, solid-SNEDDS or solid-SMEDDS (S-SEDDS, S-SNEDDS or S-SMEDDS) using liquisolid solidification procedures similar as described above. The resulting solid formulations in turn can be worked into various solid or semisolid dosage forms (tablets, pellets, capsules, creams, transdermal systems, etc.).